Growth hormone signaling via PI3K and MAPK
Growth hormone (GH or Somatotropin) is a major
growth-promoting and metabolic regulatory hormone. Interaction of
Somatotropin with Growth hormone receptor
(GHR), by virtue of receptor dimerization, causes activation
of GHR associated cytoplasmic tyrosine kinase, Janus kinase 2
(JAK2) .Almost all downstream
signaling pathways utilized by Somatotropin require
JAK2 activity , .
Somatotropin effects include stimulation of amino acid
transport, protein synthesis, glucose transport, lipogenesis, gene expression,
mitogenesis, prevention of apoptosis, differentiation and reorganization of cytoskeletal
Somatotropin activates Mitogen activated protein kinase 1
(ERK2) ,  and Mitogen
activated protein kinase 14 (p38alpha (MAPK14))  via JAK2-associated adapter proteins Src homology
2 domain containing transforming protein 1 (Shc) and Growth
factor receptor-bound protein 2 (Grb2) .
Somatotropin stimulation results in the assembly of a
Shc-GRB2- Son of sevenless
homologes (SOS) complex with the resultant activation of
v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-RAS)
and subsequent engagement of the -raf-1 murine leukemia viral oncogene homolog 1
protein kinase kinase 1 (MEK1(MAP2K1)/
ERK2 pathway . In response to
Somatotropin signaling, ERK2
phosphorylates and activates several transcription factors including Activating
transcription factor 2 (ATF-2), ELK1, member of ETS oncogene
family (Elk-1) and ELK4, ETS-domain protein ()
Elk-4. Ternary complex factors
Elk-1 and Elk-4 mediate
Somatotropin -induced transcription of Early growth response
factor-1 (EGR1), v-fos FBJ murine osteosarcoma viral
oncogene homolog (c-Fos) and Jun B proto-oncogene
(JunB) genes , .
Activation of p38alpha (MAPK14) by
Somatotropin is the
JAK2-dependent process involving PTK2B protein tyrosine
kinase 2 beta (Pyk2(FAK2)) and Mitogen-activated protein
kinase kinase kinase 4 (MEKK4(MAP3K4))/
Mitogen-activated protein kinase kinase 3
(MEK3(MAP2K3)) activation .
p38alpha (MAPK14) is required for
Somatotropin -induced ATF-2,
DNA-damage-inducible transcript 3 (C/EBP
zeta) and CCAAT/enhancer binding protein (C/EBP), beta
(C/EBPbeta) transcription activity, reorganization of the
actin cytoskeleton and mitogenesis .
A critical transcription factor of Somatotropin action is
the transcription activator C/EBPbeta that is necessary for
transcription of v-fos FBJ murine osteosarcoma viral oncogene homolog
(c-Fos) gene . Regulation of
C/EBPbeta activity is mediated both by
p38alpha (MAPK14) and
Phosphatidylinositol 3-kinase (PI3K)/ V-akt murine thymoma
viral oncogene homolog 1 (AKT(PKB)) pathways.
Somatotropin -dependent tyrosyl phosphorylation of
adaptor proteins Insulin receptor substrates 1 and 2 (IRS-1,
JAK2 leads to the increased association of
Shc/GRB2 complex, and the
association of IRS-1 and IRS-2
with the Phosphoinositide-3-kinase, regulatory subunit 1
(PI3K reg class IA (p85 alpha)) and Protein
tyrosine phosphatase, non-receptor type 11 (SHP-2) . PI3K reg class IA (p85-alpha) can bind directly to
the phosphorylated tyrosine residues at the carboxyl-terminal part of the
Somatotropin receptor, providing a direct alternative route
for the activation of Phosphoinositide-3-kinase, catalytic, alpha polypeptide
(PI3K cat class IA (p110-alpha)) .
Somatotropin activates serine/threonine kinase
AKT(PKB) in a PI3K-dependent
manner . AKT(PKB) inhibits Glycogen synthase
kinase 3 beta (GSK3 beta) and attenuates its negative
control of C/EBPbeta activity.
GSK3 beta pathway mediates signaling between
Somatotropin receptor and the nucleus, promoting activation
of C/EBPbeta .
Somatotropin also initiates
PI3K/ GSK3 beta signaling to
deliver an antiapoptotic signal .
Somatotropin -stimulated Ribosomal protein S6 kinase,
70kDa, polypeptide 1 (p70 S6 kinase 1)
activation is probably mediated through a
PI3K/ AKT(PKB) pathway
including Tuberous sclerosis 2 (Tuberin)/ Ras homolog
enriched in brain (RHEB2)/ FK506 binding protein
12-rapamycin associated protein 1 (mTOR) pathway 
Cytokine receptor signal transduction is controlled by limitation of the magnitude and
duration of the signal through negative regulation. The mechanisms by which
Somatotropin signaling can be attenuated include tyrosine
dephosphorylation of JAK2 and IRS-1
by phosphatases Protein tyrosine phosphatase, non-receptor type 6
(SHP-1) and SHP-2, and cleavage
of GHR by ADAM metallopeptidase domain 17
(ADAM17) with subsequently GHR
inactivation , , .
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